281

CONTINUED MEDICAL EDUCATION

L

Buruli ulcer
Úlcera de Buruli
Manuela Boleira 1 Omar Lupi 2
Linda Lehman 3 Kingsley Bampoe Asiedu 4

5
Ana Elisa Kiszewski

Abstract: Buruli ulcer, an infectious disease caused by Mycobacterium ulcerans, is the third most preva-
lent mycobacteriosis, after tuberculosis and leprosy. This atypical mycobacteriosis has been reported in
over 30 countries, mainly those with tropical and subtropical climates, but its epidemiology remains
unclear. The first autochthonous cases of infection in Brazil have recently been described, making this
diagnosis important for Brazilian dermatologists. Clinical manifestations vary from nodules, areas of
edema, and plaques, but the most typical presentation is a large ulcer, usually in the limbs. Despite con-
siderable knowledge about its clinical manifestations in some endemic countries, in other areas the
diagnosis may be overlooked. Therefore, physicians should be educated about Buruli ulcer, since early
diagnosis and treatment, including measures to prevent disability, are essential for a good outcome.
Keywords: Buruli ulcer; Mycobacterium infections, atypical; Mycobacterium ulcerans; World Health
Organization

Resumo: A úlcera de Buruli, uma doença infecciosa causada pela Mycobacterium ulcerans (M. ulcer-
ans), é a terceira micobacteriose em ocorrência, após a hanseníase e a tuberculose. Essa micobacte-
riose atípica tem sido relatada em mais de 30 países, principalmente, nos que têm climas tropicais e
subtropicais, mas a sua epidemiologia permanece obscura. Recentemente, os primeiros casos autóc-
tones do Brasil foram relatados, fazendo com que dermatologistas brasileiros estejam atentos a esse
diagnóstico. O quadro clínico varia: nódulos, áreas de edema, placas, mas a manifestação mais típica
é uma grande úlcera, que ocorre, em geral, nas pernas ou nos braços. Apesar do amplo conhecimen-
to quanto ao seu quadro clínico em países endêmicos, nas outras áreas, esse diagnóstico pode passar
despercebido. Assim, médicos devem ser orientados quanto à úlcera de Buruli, pois o diagnóstico pre-
coce, o tratamento específico e a introdução de cuidados na prevenção de incapacidades são essenci-
ais para uma boa evolução.
Palavras-chave: Infecções atípicas por mycobacterium; Mycobacterium ulcerans; Organização Mundial
de Saúde; Úlcera de Buruli

Approved by the Editorial Board and accepted for publication on 19.03.2010.

* Work conducted at the Dermatology Service of the General Polyclinic of Rio de Janeiro (RJ), Brazil, and Global Buruli Ulcer Initiative - World Health
Organization (WHO).
Conflict of interest: None / Conflito de interesse: Nenhum
Financial funding: None / Suporte financeiro: Nenhum
1
Postgraduate Course in Dermatology, General Polyclinic of Rio de Janeiro - Rio de Janeiro (RJ), Brazil.
2
Professor (Ph.D.) of Dermatology - Federal University of Rio de Janeiro State (UniRio); Immunologist - Federal University of Rio de Janeiro (UFRJ); Professor
of Dermatology - Carlos Chagas Postgraduate Medical Institute/General Polyclinic of Rio de Janeiro - Rio de Janeiro (RJ), Brazil.
3
Technical Consultant to the American Leprosy Missions; Physician - Colorado State University (CSU); B.S. in Occupational Therapy; M.S. in Public Health -
Emory University, Atlanta/USA; Consultant to the Leprosy Control Program in Brazil and the World Health Organization (WHO) - Buruli Ulcer Program (BU) -
Belo Horizonte (MG), Brazil.
4
Coordinator of the Global Buruli Ulcer Initiative/GBUI), World Health Organization (WHO) - Geneva - Switzerland.
5
Professor (Ph.D.) of Dermatology - Health Sciences Federal University of Porto Alegre; Dermatologist at Santa Casa Hospital Complex of Porto Alegre - Porto
Alegre (RS), Brazil.

©2010 by Anais Brasileiros de Dermatologia

An Bras Dermatol. 2010;85(3):281-301.

282 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
INTRODUCTION
Buruli ulcer (BU), an infectious disease caused
by Mycobacterium ulcerans, 1 is one of the most neg-
lected tropical diseases. It is the third mycobacteriosis
in prevalence, after leprosy and tuberculosis. M.
Ulcerans is capable of producing mycolactone, an
immunomodulatory macrolide toxin that causes tis-
sue necrosis 2,3 and destroys the skin and soft tissues
with the formation of large ulcers, often in the arms or
legs. In general, the clinical presentation of ulcer is
associated with a delay to seek medical treatment 4
and with lack of adequate treatment. Patients not
treated early often suffer from functional disabilities
in the long run, with joint movement impairment,
which restricts their ability to execute and participate
in daily activities.5,6
Early diagnosis and a specific treatment for BU
associated with interventions that prevent disabilities
are crucial for satisfactory treatment results. 7,8 When
necessary, surgery associated with antimicrobial
therapy is the recommended treatment. 7 When
extensive lesions and complications exist, the patient
may need long periods of hospitalization, with severe
socioeconomic and psychosocial implications.9,10
Buruli ulcer has been reported in more than 30
countries, especially in those with tropical and
subtropical climate, but it can also occur in a few
countries where the disease has not yet been
recognized. The number of reports of affected
patients grew considerably over the last few years. 7
Despite the several cases described, the epidemiology
of BU remains unclear, even in endemic countries. 8
Limited knowledge of the disease, its focal
distribution, and the fact that it affects mainly poor
rural communities contribute to the low notification
of cases. 2
HISTORY
In 1897, Sir Albert Cook, a British physician
who worked at the Mengo Hospital in Kampala,
Uganda, described skin ulcers that were clinically
consistent with Buruli ulcer (BU), 7 but the first
detailed description of the disease caused by
Mycobacterium ulcerans is attributed to MacCallum
et al. in Australia in 1948. 11 In 1950, in the Belgium
Congo (current Democratic Republic of Congo), the
first African case was reported and, in that same year,
Fenner identified the bacillus and named it
Mycobacterium ulcerans. 1 Since 1959, several
authors have described many patients with this
disease in tropical and subtropical regions of Central
and West Africa. 7,12 In the Americas, it is a rare disease
and very few cases have been reported. This
mycobacteriosis received several names according to
the place where it occurred or was observed. For
An Bras Dermatol. 2010;85(3):281-301.
instance, it was called Bairnsdale ulcer in Australia,
Buruli ulcer in Uganda, and Tora and Mexican ulcer in
Mexico. 12 The first Brazilian case was reported by do
Santos et al. only in 2007. 13
In 1998, after an international conference
organized by the World Health Organization about the
control of and research in Buruli Ulcer, held in
Yamoussoukro, Côte d’Ivoire (Ivory Coast), the Global
Buruli Ulcer Initiative was implemented. The initiative
remains active until today, including several research
projects in different African countries, where Buruli
ulcer is an endemic disease.
EPIDEMIOLOGY
Buruli ulcer frequently affects individuals who
live close to water bodies – slow flowing rivers, ponds,
swamps, and lakes; however, cases of the disease have
been reported after flooding. Activities that are
developed close to the water, such as farming,
constitute risk factors. Protective clothing appears to
reduce the risk of contracting the disease. 7,8 In Benin,
an inverse relationship between the prevalence of the
disease and how far the patient lived from a river was
found. The prevalence gradually increased from 0.6 to
32.6/1000 when the distance to a river shortened by
10 km. 14
All ages and genders are affected, but most
patients are children younger than 15 years, 14,15,16 with
peak age of onset between 10 and 14 years. In adults,
it is between 75 and 79 years. 14 The high rate of
detection in elderly patients may be associated with
the reactivation of a latent disease. 17 A study showed
that even though there are no gender differences
among children and adults, men older than 59 years
had a higher chance of developing BU than women. 17
This difference may be related to professional
activities and differences in access to health services. 14
Buruli ulcer has been reported in 30 countries
from Africa, the Americas, Asia and Western Pacific,
especially in tropical and subtropical regions (Figure
1). The disease is a public health problem in Uganda,
Nigeria, Gabon, Ghana, Cameroon, Liberia, Côte-
d’Ivoire, Malasia, Papua New Guinea, Togo, French
Guiana, and Republic of Benin. 7, 12 In Côte-d’Ivoire,
approximately 15,000 cases have been registered
since 1978. In Benin, nearly 15% of the population is
affected. In 1999, 6,000 new cases were reported in
Ghana. 18 A few cases reported in North America and
Europe were associated with international travelers. 19
Some cases have been reported in China, but the
extension of the disease is unknown. In the Americas,
the disease appears to be more common in the French
Guiana (although fewer than 200 cases have been
reported in 35 years) than in Suriname, Mexico or
Buruli ulcer
Endemic countries
Areas with high incidence of Buruli ulcer disease
FIGURE 1: Geographical distribution of Buruli Ulcer
Modified Source: van der Werf et al.8
Peru, where very few cases have been confirmed –
fewer than 10 cases per country over the last 50 years.
These numbers may be only an indication of the pres-
ence of the disease, but do not reveal the extent of the
problem. 8
The first Brazilian case was reported in 2007. A
65-year-old patient was seen at a health center in
Brasilia showing two years of clinical evolution of BU
associated with osteomyelitis. The patient lived in a
rural area close to a water body, where the climate is
hot and humid. Initially, leishmaniasis, a common dis-
ease where the patient lives, was wrongly diagnosed.
After a positive culture for M. ulcerans from skin and
bone tissue samples, the diagnosis of BU was con-
firmed. 13 Despite being the first Brazilian case of BU,
similarities between the climate, vegetation, and
habits in Brazil and endemic countries suggest that
Brazil may be a focus of the disease. Health profes-
sionals’ lack of knowledge about the disease makes
the identification and epidemiological monitoring of
BU difficult in Brazil.
The second case, probably originary from the
Brazilian territory, was published by McGann et al. in
November of 2009. It refers to an English tourist who
contracted the disease after a visit to the Brazilian
Pantanal region, 20 which shows that the disease may
be more of a reality than imagined. Cases from non-
endemic countries are very rare. In the literature,
8,21,22
only
21 such cases have been reported so far, including
the last Brazilian case. One explanation for them
283
could be immigration from an endemic country for
BU to non-endemic areas. The disease could be con-
tracted in the country of origin or by a traveler from a
non-endemic country. Infection by Mycobacterium
ulcerans is among the main ulcers diagnosed in trav-
elers to West Africa, Central America and other
Western countries, together with leishmaniasis, diph-
theria, and profound mycoses. 19,21 Despite advanced
knowledge about the clinical symptoms of BU in
endemic countries, in other areas this diagnosis may
be overlooked. Therefore, physicians should be aware
of its symptoms, since early diagnosis and proper
treatment help prevent functional disabilities result-
ing from the infection. BU is probably endemic in a
broader area than often considered.
The exact prevalence of the disease is unclear
due to lack of knowledge about the disease among
health professionals and the population in general.
This leads to significant undernotification. People
who are mostly affected by the disease live in remote
rural areas, with little access to the health system.
There is great variation in the clinical presentation of
the disease, which makes confusion of BU with other
diseases and tropical ulcers common. In addition,
there is no compulsory notification in many countries.
Based on various studies, it is now clear that
there is a relationship between BU and water, but the
precise form of transmission of M. ulcerans has not
been established. An environmental factor not yet
identified associated with slow flowing water, to
An Bras Dermatol. 2010;85(3):281-301.
284 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
which populations that live close to a water body are
exposed, is thought to exist. There are reports of a
likely transmission by mosquito or insect bites. 22-26 A
research study suggests that in Africa some water
insects of the order Hemiptera (Naucoridae and
Belostomatidae) may harbor M. Ulcerans in their sali-
vary glands and transmist the disease to animals
(Figure 2). A study showed that infected Naucoris
mosquitoes transmit the pathogen to rats through bit-
ing, in addition to being naturally colonized by M.
Ulcerans in endemic areas. 23,24,25 These insects can fly
many kilometers from their starting point and this
may explain why patients who do not live close to a
water body can get infected, but not as often as those
who live closer to ponds and swamps.
More recent data from Australia suggest that
salt marsh mosquitoes test positive for M. Ulcerans
DNA, although transmission by this type of insect has
not been recognized. Further research is in progress
to establish the exact role of insects and other factors
in the transmission of the disease to humans. If this is
confirmed, BU will be the only disease caused by
mycobateria that is transmitted by insects. 7,24,25,26
Inoculation also appears to occur through trau-
ma. 27 In this case, skin contamination would occur as
a result of direct exposure to still water, gases from
lagoons and surface of ponds or contaminated
objects. M. Ulcerans can enter the human body
through several types of trauma, from mild ones such
as a hypodermal injection, to severe, like landmine
injuries, snake or even human bite. Two cases of
human bite have been reported and this exemplifies
patient-to-patient transmission.28,29
A change in the epidemiology of BU has been
A B
FIGURE 2: Acquatic insects naturally infected with Mycobacterium
ulcerans; A. Naucoris fl avicollis (size 1·5 cm); B. Belostoma cordof-
na (size 10 cm)
Source: Wansbrough-Jones M et al.2
An Bras Dermatol. 2010;85(3):281-301.
attributed to flooding, population growth, mining,
extraction of wood from tropical forests, and river
damming, but there is no evidence of this causal asso-
ciation. Hypotheses consider that M. ulcerans is intro-
duced into new regions by insects, human beings or
other animals. Alternatively, the organism can be
widely distributed in the environment, in low num-
bers, but they significantly increase after certain
events, such as deforestation and flooding. 16 Recent
research studies suggest that the prevalence of BU in
Uganda appears to have reduced significantly. In this
country, the damming of Lake Vitoria dried the
swamps at the margin of the Nile, and this may have
contributed to the dramatic reduction of the inci-
dence of the disease. 14
IMMUNOLOGY AND ETIOPATHOGENY
M. ulcerans is an acid-alcohol resistant bacillus
(BARR) predominantly extracellular. Current data sug-
gest that this mycobacterium does not exist freely in
the environment, as previously thought. It probably
occupies a specific niche within acquatic environ-
ments (for instance, small acquatic animals), from
where it is transmitted to humans by an unknown
mechanism.7 Although slow growing, M. ulcerans can
be cultured on media used for mycobacteria (such as
Lowenstein-Jensen medium) provided the incubation
temperature is kept between 29-33 ° C (lower than
that for M. Tuberculosis), microaerophilic environ-
ment, and pH between 5.4 and 7.4. There is a wide
variability of data about the success of isolation from
clinical samples. Reference laboratories have reported
high rates of success in clinically confirmed cases
using improved transportation and decontamination
methods. 8
There is some variation among strains of M.
ulcerans from different geographical areas of Africa,
the Americas, Asia, and Australia (Figure 3), but the
relationship between these various strains and viru-
lence in humans has not been established. 8 The devel-
opment of polymerase chain reaction (PCR) to
promptly identify M. ulcerans in clinical and environ-
mental samples has improved the diagnosis and com-
prehension about the epidemiology of BU. The PCR
technique identified repeated DNA sequences in the
genome of M. ulcerans, IS2404. 8,30 A direct relation-
ship between the virulence of M. ulcerans and the
number of repeated IS2404 sequences appears to
exist. 31
Mycolactone is a heat-stable exotoxin,
lypophilic, that belongs to the group of macrolides
and causes extensive, chronic, and necrotizing dam-
age to the papillary dermis, subcutaneous fat, and
muscles (fasciae and bones are sometimes affected),
resulting in derformity and disability. The molecule is
Buruli ulcer
FIGURE 3: Geographical distribution of the different strains of
Mycobacterium ulcerans
Modified source: van der Werf et al.
8 inhibition of the production of Th1-interleukin (IL) 12
active in extremely low concentrations and is not pres-
ent in laboratory cultures. 16
Mycolactone molecules, when injected in labo-
ratory animals, are capable of producing massive
necrosis similar to what is observed when these ani-
mals are inoculated with M. ulcerans. With the full
genome sequencing of M. ulcerans, it became evident
that the genetic information for mycolactone synthesis
is synthesized from a 174 kb plasmid known as
pMUM001. This makes M. ulcerans the only mycobac-
terium whose virulence is mediated by a plasmid.
Mycobacterium marinum and M. ulcerans are phylo-
genetically close, sharing from 98 to 99.8% of their
genetic material. 32 The molecular finding that most
clearly separates these two species is the production
of mycolactone by M. ulcerans. 8,16,31,33 Another
mycobacterium, M. Lifandii, isolated from frogs in
West Africa, is a pathogen associated with M. ulcerans
and M. Marinuns. M. Liflandii also presents the
IS2404 sequence and all the genes that codify myco-
lactone, except the one that codifies monooxygenase
p450. 2 M. Liflandii can produce ulcers similar to BU
in frogs. 8
M. ulcerans strains isolated in particular
regions show remarkable similarity, but important dif-
ferences in the production of mycolactone according
to geographical areas have been identified. This may
reflect regional differences in the clinical presentation
and virulence of M. ulcerans. This macrolide has been
shown to be the main virulence factor and presents
cytotoxic, analgesic, and immunosupressive activity in
the infection caused by M. ulcerans. 33
The various strains of M. ulcerans produce a
macrolide family with identical biological activity, but
with different potency. 34 The first type of macrolide
285
identified was mycolactone A/B, followed by a family
of variants of this toxin (mycolactones C, D, and E).
Studies compared strains of M. ulcerans from differ-
ent continents and verified that mycolactone A/B was
the most powerful macrolide. 35 African strains and
one from Malasia produced more mycolactone vari-
ants (at least four variants in addition to types A/B).
This could contribute to greater cytopathogenicity of
this particular strain. 36 Therefore, a region with more
extensive and disseminated BU cases is found with
higher frequency in Africa, where mycolactones A/B
are more abundant. This is different from Australia,
where mycolactone C appears more often than myco-
lactones A and B.
In vitro studies have shown that the immunosu-
pressive activity of mycolactone occurs through the
cytokines, interferon (IFN)-alpha, and suppression of
the production of tumoral necrosis factor (TNF) by
monocytes. These cytokines are important in the con-
trol of mycobateria infection. 37 Studies on tuberculo-
sis and leprosy have shown that Th2 cytokines (IL-4,
IL-13) and antiinflammatory cytokines, such as IL-10
and tumoral growth factor (TGF), have a negative
effect on the control of mycobacteria proliferation. 38,39
Kiszewski et al. showed that in ulcers with granulomas
there is a significantly higher expression of IFNγ and
lower bacillary load. However, the cytokine profile
found in BU without granulomas was similar to the
one found in active progressive tuberculosis, in which
there is reduction of Th1 cell funtion and increase of
Th2 activity, associated with a high production of IL 10
and TGFβ. 34,38 This could indicate that the presence of
granuloma signals better immunological protection. 34
Hence, it appears that there is a mixed model of pro-
and antiinflammatory cytokines in areas of ulcerative
lesions of BU, which vary based on the evolution of
the disease. Recent ulcerated lesions have a predomi-
nant immunosuppressive cytokine profile, with high
bacillary load, whereas old ulcers have a combination
of cytokines with predominance of IFNγ and low bacil-
lary load and typical granuloma. In addition, dissemi-
nated disease and osteomyelitis have been associated
with defects in the formation of granulomas. 40,41
Many healthy individuals in endemic areas for
Buruli ulcer show a specific humoral immune
response to M. ulcerans, suggesting that the disease
thrives only in a limited group of individuals who have
been infected by M. ulcerans. The immune response
mediated by Th1 lymphocytes is protective against
BU; however, Th2, which is targeted to the production
of antibodies, does not control the disease. Humoral
immune response with production of IgM antibodies
appears to be more frequent in patients with active
ulcers than in their relatives. Co-infection by HIV has
An Bras Dermatol. 2010;85(3):281-301.
286 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
not been reported as a risk factor, but more severe
clinical forms of BU have been described in seroposi-
tive patients. 42 A few individuals could escape the dis-
ease due to an individual protection centered in a
cellular immune response.
HISTOPATHOLOGY
It is possible to divide BU into four
histopathological stages of evolution: 43
• Non-ulcerated necrotic stage: the epidermis is
intact, but it is often hyperplastic. The upper dermis is
usually preserved, but it can show various degrees of
collagen degeneration, edema, and discreet infiltra-
tion of inflammatory cells. Vasculitis, with occlusion of
vessels by thrombus, can also be observed. In this
stage and in the initial ulcerative phases, coagulation
necrosis in the lower portion of the dermis, subcuta-
neous tissue, and fascia is easily identified. In these
areas, predominantly extracellular BAAR form clusters
that are easily detected in the center of the lesion in
the deep layers of the dermis and in the adipose pan-
iculus. Calcification can also be detected. Another
finding is the presence of denucleated adipose cells,
called “ghost cells”.
• Ulcerated necrotic stage: there is loss of epi-
dermis and reepitalization attempt in the borders of
the ulcer. The adjacent epidermis is often hyperplastic
(pseudoepitheliomatous hyperplasia). The base of the
ulcer exposes the dermis with necrotic material and
fibrosis. Necrosis of the subcutaneous tissue and der-
mal collagen, with formation of “ghost” cells, is
accompanied by edema, minimal inflammation, and
presence of numerous, predominantly extracellular
BAAR in clusters. Necrosis by coagulation affects the
subcutaneous cellular tissue and fascia similarly to the
non-ulcerative phase. Vasculitis and extensive areas of
calcification in the lower portion of the dermis are fre-
quently observed (Figures 4 A, B, C, and D).
• Initial healing stage (of organization and
granulomatous): it is characterized by the start of a
granulomatous response in the dermis and subcuta-
neous cellular tissue. Epithelioid cells, Langhans giant
cells and lymphocytes are present in this phase.
Eventually, these cells rearrange to form tuberculoid
granulomas.
Foamy macrophages, lymphocytes, and plas-
matic cells are sometimes seen in the margins of
necrotic tissue. The appearance of granulous tissue
indicates the beginning of the ulcer healing process.
In this stage, BAAR are rarely found in the histopatho-
logical examination. 39
• Late healing stage - fibrosis and atrophic epi-
dermis.
Histopathological findings are considered
unspecific; however, considering the different find-
An Bras Dermatol. 2010;85(3):281-301.
ings altogether, it is estimated that the sensitivity of
the anatomopathological exam is around 90%. The
sensitivity of the Ziehl-Neelsen staining procedure is
between 40 to 80%. 42 In conclusion, the most charac-
teristic findings of a histopathological study of BU
lesions are necrosis of the subcutaneous tissue and of
the dermal collagen accompanied by minimal inflam-
mation (despite the extensive necrosis observed), and
predominantly extracellular acid-alcohol resistant
bacilli (BAAR). Neutrophils can be found in the
necrotic material. This mild inflammation could be
explained by the action of exotoxin, which causes
necrosis of adipose cells and of the inflammatory infil-
trate. 44
CLINICAL PROFILE
Non-tuberculoid mycobacteria are present in
the environment and are in permanent contact with
humans and animals. Therefore, the colonization of
clinically healthy individuals by these bacteria is very
common. 14 Contact with M. ulcerans may result in
the colonization of healthy tissue without infection.
Evolution to the clinical manifestation of the disease
depends primarily upon the host’s defenses. Another
hypothesis is the self-resolution of the primary infec-
tion, being thus never noticed. The disease may cause
subclinical symptoms or even develop an asympto-
matic profile, remaining latent, as shown in figure 5.
Later, the patient may have the latent focus activated
and manifest the clinical symptoms and signs of the
disease. Sometimes, only a superficial trauma is nec-
essary for the reactivation of the infection focus, with
a shorter incubation period (about 15 days) than the
typical one, between 2 and 3 months. 14Australian
authors have reported the case of a patient, most like-
ly carrying the latent disease, who after immunosup-
pressive therapy with corticosteroids developed dis-
seminated BU. 45
The disease caused by M. ulcerans has a spec-
trum of clinical forms mostly associated with the time
between the onset of the disease and when the
patient seeks a health center for diagnosis. The aver-
age incubation period is from two to three months. 14
After primary infection, the disease can remain local-
ized or disseminate. Many factors contribute to the
evolution of the disease, such as the immunological
status of the host, the size and depth of the inocula-
tion site, and the virulence of the strain. 14,22 The pre-
ulcerative form of the disease often does not make the
patient seek medical assistance and this period may
vary from a few weeks to months.
Clinically, BU can be divided into pre-ulcerative
stage (papule, nodule, plaque, and diffuse edema)
and ulcerative stage, which may be represented by
small ulcers (smaller than 5 cm) and large ulcers (lar-
Buruli ulcer 287

A B

C D

FIGURE 4: A. HE 100X. Denucleated adipose cells - “ghost cells' - accompanied by discreet mononucleate inflammatory infiltrate; B. HE 100X.
Presence of coagulation necrosis with calcification areas; C. ZN 200X. BAAR grouped in extracellular environment forming clusters; D. ZN
400X. Grouped BAAR

ger than 5 cm). It can also be classified into localized
disease (papule, nodule, and ulcer) and disseminated
disease (plaques, diffuse edema, and metastasis). 14,43
The initial stage of Buruli ulcer often starts with
a painless and mobile skin nodule, with less than 5 cm
of diameter, that ulcerates usually after a few weeks. It
forms an ulcer with poorly demarcated borders, mak-
ing it appear smaller than it really is (Figure 6A). In the
Australian population, 16 it is more common for
patients to notice a small pustule or papule, often
attributed to insect bites, without the nodular phase.
This papule often has less than 1 cm of diameter and
is accompanied by erythema in the adjacent skin. This
form of the disease has not been reported in Africa. 14
The ulcer develops due to perforation of the necrosis
above the epidermis There is no pain or, if present, it
is reported as very mild. Borders are characteristically
poorly demarcated, undermined, and there is edema
in the adjacent skin. The ulcer may remain small, with
1 to 2 cm of diameter, and it is more susceptible to
self-resolution (Figure 6B). However, ulcers frequent-
ly become larger and destroy the skin around them.
They may affect bone tissue and develop into dissem-
inated disease (Figure 6C). Their borders are hyper-
pigmented and their background, necrotic. The dis-
ease can also present with a large area of marked
induration, diffuse edema in the legs and arms or a
well-demarcated plaque (Figure 7A). 7 Plaques are
raised, hard, painless and with a certain degree of
depigmentation or spotted erythema. They can have
more than 2 cm of diameter, possibly reaching 15 cm.
They can develop into large ulcers with irregular bor-
ders. When there is only one edema, the profile is
more diffuse, without a Godet sign, and with poorly
demarcated borders. Edematous lesions can affect an
entire limb and a large portion of the trunk. After a
few days or weeks exulcerations are formed in these
areas. 7
Lesions can develop in new areas, distant
from the original lesion, which characterizes a
metastatic form of the disease. This evolution of the
clinical condition can be explained by the lymphatic
or blood system, especially in relation to the dissemi-
nated form of the disease. 14
Strains of M. ulcerans isolated from different
clinical forms of the disease in a particular geographi-

An Bras Dermatol. 2010;85(3):281-301.

288 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE

Photo courtesy of: P. Couppié/French Guiana, H. Guerra/Peru

A

FIGURE 5: Buruli ulcer. Clinical Profile. Flowcharts of the clinical

presentations of the disease
Modified source: Portaels F et al.14

cal region appear identical, suggesting that host fac-

tors may play an important role in the establishment
of the various clinical presentations. 7, 16 Due to the
local immunossupressive properties of mycolactone C
or, perhaps as a consequence of other unknown
mechanisms, the disease evolves without pain, fever
or systemic inflammatory response. 15 This may partly
explain why affected individuals do not seek immedi-
ate treatment. Nevertheless, without treatment, large
ulcers develop. The base of the initial ulcer often con-
tains a whitish, frothy-like secretion; sometimes it can
form crusts. The skin surrounding the lesion becomes
increasingly pigmented. 7 When ulcers are large, they
may affect an entire extremety or a large portion of
the trunk (Figure 7B).
One of the consequences of an extensive ulcer
is the fact that it may affect bone tissue, increasing the
risk of osteomyelitis, 16, 46 and later lead to deformities
FIGURE 6: A. Initial nodular lesion of Buruli Ulcer; B. Small ulcer-
and even amputations. Involvement of other organs is ated lesions; C. (old10) Large ulcerated lesion with undermined
extremely rare. 22 Metastatic osteomyelitis has also borders
been reported and it can affect approximately 10% of
the patients with BU. It is directly proportional to the
number of skin lesions. 16 patient’s ability to perform daily activities and making
Involution of lesions may result in atrophic participation in work activities difficult (Figure 8). 47,48
sequelae or symmetrical scars, sometimes hypotroph- The cosmetic aspect of a scar may also cause social
ic or keloid-like, with contractures and impairment of problems, withdrawing the patient from routine activ-
the function of limbs when localized near or over ities. Permanent disabilities affect around one fourth
joints. Scars may restrict limb movement, limiting the of the patients. 7 The disease may affect any part of the

An Bras Dermatol. 2010;85(3):281-301.

 Buruli ulcer
Photo courtesy: H. Assé/ Côte d'Ivoire
FIGURE 7: A. Edematous area affecting the entire upper limb; B.
Large ulcerated lesion affecting the entire lower limb
body, but in about 90% of the cases lesions develop in
the limbs, with nearly 60% of all lesions occuring in
lower limbs. 7,8
Differently from tuberculosis (TB), there is no
evidence that HIV infection predisposes individuals to
Buruli ulcer. 12 But the disseminated form of the dis-
ease associated with HIV has been previously report-
ed. 49, 50 There is little seasonal variation in the inci-
dence of the disease, 8 but studies have shown that in
Australia, Papua New Guinea, Cameroon, Uganda,
Ghana, and Côte D’Ivoire there is a slight higher inci-
dence of BU in relatively dry periods. 51
Factors associated with poor nutrition, such as
hypoproteinemia or anemia, have been associated
with the development of symptoms and the suscepti-
bility of the host to BU. 16,51 This could be explained by
a defficiency in micronutrients such as zinc, which
lowers the defenses against bacterial toxins and
reduces the function of T cells and immunity mediat-
ed by cells. In addition, lack of knowledge about the
disease, poor hygiene, infrastructure problems such
289
as poor living conditions or lack of sewage and med-
ical resources, little access to health services, risky cul-
tural practices, poor nutrition, and general poverty
increase the risk of contact with and infection by
aggressive pathogens. 51
DIFFERENTIAL DIAGNOSES
Differential diagnosis depends upon the stage
of presentation of the disease and relevant conditions
in the area where the patient lives. 8 In a few endemic
countries, particularly in West Africa, Buruli ulcer may
be confused with onchocercoma (onchocercosis nod-
ules), noma (cancro oris), bouba, nodular form of
leishmaniasis, spinocellular carcinoma, Kaposi sarco-
ma, cutaneous tuberculosis, pyoderma gangrenosum,
leprosy, and syphilis. 8,14
Plaque and edematous BU can simulate pro-
found mycosis, erysipelas, bruise, lupus vulgaris,
eczema, disseminated sarcoidosis with plaques, necro-
biosis, lipoma, epidermal cyst, lymphadenitis or lym-
phadenopathy, and hydradenitis. The differential diag-
nosis of the edematous form of the disease is
osteomyelitis due to other causes, pyomyositis, ele-
phantiasis, renal or cardiac insufficiency edema, ane-
mia, malnutrition and tumor lymphatic compression. 14
Ulcerative lesions may be confused with tropi-
cal ulcer (lower limbs). 8 However, tropical ulcers are
often painful and found only in the lower part of the
legs. Leishmaniasis is an important differential diagno-
sis in South America, and spinocellular carcinoma can
also present as ulcers. The undermined border of the
ulcer orients to the diagnosis of pyoderma gangreno-
sum. There is still the possibility of diagnostic confu-
sion with necrotizing fasciitis, sporotricosis, anthrax,
and other tropical phagedenic and stasis ulcers. 14
In the healing form, differential diagnosis
should be made with scars resulting from third degree
burns and healing lesions of chronic osteomyelitis. 14
DIAGNOSIS
Buruli ulcer is frequently diagnosed and treated,
based on clinical information, by experienced health
professionals in endemic areas. The clinical criteria for
higher suspicion of BU are 14,16,52 1) presence of chronic
lesion – weeks or months; 2) absence of fever or
regional lymphoadenopathy; 3) nodular lesion, hard
plaque or edema; 4) one or more chronic ulcers with
poorly demarcated, undermined borders or depressed
scars; 5) edema over a painful joint, suggesting bone
involvement; 6) patient younger than 15 years; 7)
patient who lives at or visited an endemic area.
Laboratory diagnoses are not commonly used
to make decisions about treatment due to logistic and
operational difficulties. 16 Even though most health
professionals in endemic regions are able to arrive at
An Bras Dermatol. 2010;85(3):281-301.
Photo courtesy of: WHO and S. Etuaful/Ghana 290 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
FIGURA 8: A. Extensive area of scar secondary to Buruli ulcer; B.
Extensive scar in the upper limb degenerating to epidermoid
carcinoma
a precise clinical diagnosis, microbiological confirma-
tion is important, whenever possible.14 This measure
helps to elucidate the real prevalence and incidence
of BU, confirm new foci of the disease, and verify
relapse or reinfection after treatment. Laboratory
diagnosis can also be used to confirm the clinical diag-
nosis retrospectively on swabs and tissues removed
during treatment, but this is rarely done. Sample col-
lection depends upon the clinical form of the disease
and the objective of the test being performed. 8,14 Two
samples are often collected per lesion. 43,53 Multiple
swabs are taken from the border of lesions, since the
center is often negative for M. ulcerans. In patients
undergoing surgery, samples should be collected
from the tissue removed for bacteriological and
histopathological analysis. 14,43 To confirm
osteomyelitis, curettage of the bone tissue should be
performed. Despite improvements in material collec-
tion techniques, access to competent laboratories to
read these exams is complicated.
Five laboratory methods to confirm the disease
An Bras Dermatol. 2010;85(3):281-301.
are often used:
• Direct Smear Examination - An examina-
tion done on swabs from ulcers or smears from tissue
biopsies that can be promptly conducted at local
health facilities where TB microscopy is also done. 7
The exam is conducted through the acid-fast (Ziehl
Neelsen) stain procedure. Nevertheless, the sensitivity
of this method is low (about 40%) 18 because M. ulcer-
ans numbers tend to decrease over time. It is impor-
tant to emphasize that the positivity of the test varies
with the clinical form of the disease. It is more useful
in the ulcerative stage, 8 but if the lesion is not ulcer-
ated, a skin biopsy is sufficient for the exam. In the
nodular form, positivity may reach 60% and in the
edematous form, it may reach up to 80%, both in the
direct examination and culture.16 It is considered by
many the easiest and most accessible method to arrive
at the diagnosis.
• Culture of M. ulcerans - A procedure done
on swabs from ulcers or tissue biopsies through the
Lowenstein-Jensen medium that takes 6–8 weeks or
more; sensitivity is approximately 20–60%. 7 It is espe-
cially difficult to culture M. ulcerans when the sample
is taken from bone tissue. 16
• Polymerase chain reaction (PCR) - A test
whose results can be obtained within two days on
swabs of ulcers or tissue biopsies; sensitivity is around
98%. 2,7 Most studies use the IS2404 sequence. 2,8 The
PCR technique has been refined with the addition of
uracil-DNA glycosylase and deoxyuridine triphosphate
to the mixture instead of deoxythymidine triphos-
phate, which reduces the risk of false positive results
due to contamination. 54 PCR with lyophilized reagents
and transportation buffers has also been developed to
overcome technical difficulties in the tropics. 54 The
positivity of PCR and histopathological tests does not
vary with the clinical form of the disease.
• Histopathology. A method that requires tis-
sue biopsies; sensitivity is about 90% and is useful for
differential diagnoses when the results of other meth-
ods are negative. It should be done with a scalpel,
thus avoiding the use of punches. The incision should
cover the border of the lesion and extend into the
subcutaneous tissue. It may be up to 90% sensitive; 7
in a study conducted in Ghana, despite having found
a sensitivity of about 82%, the authors considered this
to be the most sensitive method.53
• Fine needle aspiration: This technique is
used in cases of nodular lesions and allows the collec-
tion of material for later research, such as direct exam-
ination and culture. 14
Frequently, some laboratory methods, such as
PCR, are limited to reference and research laborato-
ries, often remote from endemic areas. Usually, in rou-
tine clinical practice cases are managed without
Buruli ulcer
microbiological confirmation. Four laboratory tests
are currently available to confirm the diagnosis of BU:
1 – direct examination of secretion with BAAR investi-
gation and Ziehl Neelsen stain or auramine O; 2 – cul-
ture; 3- PCR for the IS2404 sequence, and 4-
histopathology.14 The WHO recommends that at least
two laboratory tests be carried out for diagnostic con-
firmation, making the occurrence of false-positive and
false-negative results more difficult. A simple and fast
diagnostic test for BU is needed because the initial dis-
ease (nodule) can be treated locally and inexpensive-
ly. The WHO is reconsidering its early recommenda-
tion that two confirming tests were needed to arrive at
a conclusive dignosis. 8
TREATMENT
Sometimes localized lesions may spontaneous-
ly recede; however, without treatment, most cases of
BU result in physical deformities that lead to disabili-
ty, psychological problems, and stigmas. Early detec-
tion of active cases, proper treatment, and complete
joint movement of the affected area are essential for
the prevention of disabilities.
According to the WHO, the following are the
current recommendations for treatment: 7,8
• A combination of rifampicin and an aminogly-
coside (streptomycin/amikacin) for eight weeks as a
first-line treatment for all forms of the active disease.
Nodules or uncomplicated cases can be treated with-
out hospitalization. Side effects have been reported,
but are considered rare and are listed in Chart 1. The
recommended doses of rifampicin and streptomycin
are: rifampicin, 10 mg/kg of body weight, taken orally
and daily for eight weeks; streptomycin, 15 mg/kg of
body weight, taken intramuscularly and daily for eight
weeks (Chart 2). This drug is contraindicated for preg-
CHART 1: Main side effects associated with the drugs recommended to treat Buruli ulcer
Common side effects Probable causative drug
Anorexia, nausea, abdominal pain Rifampicin
Jaundice and hepatitis Rifampicin
(excluding other causes)
Shock, purpura, acute renal failure Rifampicin
Hypoacusis (in the absence of ear wax Streptomycin
confirmed by otoscopy)
Dizziness with vertigo and nystagmus Streptomycin
Adapted source: WHO/200448
291
nant women. Amikacin is a viable alternative if strep-
tomycin cannot be used and it is administered in the
dose of 15mg/kg of body weight, instramuscularly,
daily, for eight weeks. 52
• Surgery to remove necrotic tissue and skin
grafts to aid in healing make recovery faster and more
efficient. Surgery is performed to correct skin defects,
contractures and the function of affected joints, and
for cosmetic reasons.
• Interventions to minimize or prevent physi-
cal, emotional and social disabilities. 47,48 The best pre-
vention is to teach the population and health profes-
sionals how to diagnose and later treat the disease.
Other actions, associated with antibiotic therapy, are
needed to avoid complications and disabilities.
Education is the best guarantee that patients and their
families will learn about and participate in their self-
care from the moment of the diagnosis. The most
important measures are:
Dressings that aid in healing, preventing the
contracture of soft tissues and joints;
Exercises and positioning of the affected part to
avoid contractures;
Control of the edema;
Care with the skin and scar, keeping them
hydrated, lubricated, mobile (without adhesions), and
protected;
Participation in daily activities;
Good nutrition and diet that aid in healing;
Good hygiene, which helps to avoid infections;
Awareness that when needed, help should be
asked of others.
For a long time, the treatment of BU was exclu-
sively surgical and often mutilating. Treatment with
drugs was only implemented in 2005 with the associ-
Conduct
Continue treatment with administration of
the drug with small meals or at bedtime
Suspend treatment
Suspend treatment
Suspend treatment
Suspend treatment
An Bras Dermatol. 2010;85(3):281-301.
292 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
CHART 2: Dosages of drugs recommended to treat Buruli ulcer
Patient's body weight (kg) Rifampicin (300mg/tablet)
Dose (mg)
5-10 75
11-20 150
21-30 300
31-39 300
40-54 450
>54 600
Adapted source: WHO/2004 48
ation of rifampicin and streptomycin so that the
lesions and edema could be reduced, helping surgical
excision. 55 The surgical treatment of BU initially con-
sisted in the radical excision of all necrotic tissue and
a portion of normal tissue, followed by skin graft.
Studies have shown that antimicrobial drugs
(rifampicin, aminoglycosides, macrolides, and
quinolones) inhibit the growth of M. ulcerans in vitro
and in vivo and that treatment combinations contain-
ing aminoglycosides were more efficient than those
without this drug. 8 A previous study conducted by the
British Research Council in Uganda showed the bene-
ficial effect of clofazimine. 8 In another study in
Ghana, patients with a clinical diagnosis of the nodu-
lar form of the disease were randomized to receive
rifampicin, 10 mg/kg, and streptomycin, 15 mg/kg for
two, four, eight or twelve weeks. After these weeks, all
patients underwent surgery and skin biopsies were
analysed by PCR, culture, and histopathology. In
patients treated for two weeks, viable M. ulcerans
could still be cultured, whereas in all the patients who
were treated for at least four weeks, living bacilli
could not be isolated. Clinically, however, most
patients responded well to streptomycin and
rifampicin; in some cases, lesions receded completely. 55
Nienhuis et al. conducted a study comparing
the use of streptomycin and rifampicin for eight
weeks with the regimen of rifampicin for eight weeks
and streptomycin for four weeks, associated with the
use of oral clarithromycin for four more weeks. The
authors showed that 96% of the patients who used
streptomycin for eight weeks and 91% of those who
used streptomycin for four weeks followed by oral
clarithromycin for four weeks had their lesions healed
and were cured after a year without relapse after
antibiotic treatment. The difference between the two
therapeutic regimens was very small, suggesting that
they are both efficient. This study also demonstrated
that initial and limited lesions of BU can be effective-
ly treated without surgical procedures. 56,57 Previously,
studies showed that initial lesions removed with a
simple excision had a relapse rate of 16% after a year.
An Bras Dermatol. 2010;85(3):281-301.
Streptomycin (1g/ 2ml)
No. of tablets Dose (g) Volume (ml)
0,25 0,25 0,50
0,50 0,33 0,70
1,00 0,50 1,00
1,00 0,50 1,00
1,50 0,75 1,50
2,00 1,00 2,00
Even after evidence about the therapeutic effect of
antibiotics in the treatment of BU, 56,57 surgery is still
necessary in some cases. The type of surgical treat-
ment will depend on the clinical form of the disease.
Papules, nodules, and small ulcers are excised with
simple closure. The avoidance of aggressive surgical
procedures produces more satisfactory functional
results. 58 It has been observed that extensive and
unnecessary surgeries can damage healthy tissues and
do not prevent relapses. For patients with facial
lesions, surgery is not a treatment option. Patients
should be referred to an orthopedist when there is
bone tissue involvement.
The WHO has created a didactic division 52 into
treatment categories according to the size of the
lesion and other complications (Chart 3). The three
treatment categories seek to help manage the disease
and do not cover all of its clinical forms. A careful and
adaptive analysis of the clinical condition should be
conducted to control all forms of the disease.
Moreover, findings from Nienhuis et al. should be
considered so that unnecessary surgical procedures
can be avoided.
Complete mobility of the affected area when
diagnosis is accomplished, during, and after treatment
may prevent contractures due to the healing process.
Patients and their families should learn how to make
these movements as part of their daily self-care rou-
tine. The health team and the community health agent
must instruct patients and their families and practice
the movements with them. Most physiotherapy and
rehabilitation services are offered in reference centers
for the treatment of BU in endemic countries.
Unfortunately, access to these centers is limited, but
they are very important to complement surgical treat-
ment. 7,47 Other topical treatments have been suggest-
ed, including thermal treatment, hyperbaric oxygen
therapy, medicinal argyle, powder phenytoin, and
nitrite ointment. 8
Recurring infections are a problem, especially
in immunocompromised individuals and patients
with disseminated disease. They also occur frequently
Buruli ulcer 293

CHART 3: Division in categories to aid in the treatment of the Buruli ulcer patient

Categoria Form of disease Treatment Primary Secondary Health system Diagnosis

objective objective level
I Recent small lesions For papules and nod- Precise clini-
(nodules, papules, ules, if immediate exci- Cure without Reduction Community cal diagnosis
plaques, and ulcers sion is possible, start surgery, and preven- health centers and laborato-
with less than 5 cm antibiotic therapy at excluding tion of recur- and district ry exams
of diameter) least 24 hours before debridement rences hospitals
the procedure and con- of necrotic tis-
tinue for 4 more weeks sue
Alternatively, treat all
lesions in this category
with antibiotics for 8
weeks

II Non-ulcerative and Treat with antibiotics Reduction of Reduction District and ter- Precise clini-
ulcerative plaques for at least 4 weeks the extension and preven- tiary hospitals cal diagnosis
and edematous forms after surgery (if need- of surgical tion of recur- and laborato-
Extensive ulcerative ed) followed by 4 more excision rences ry exams
lesions with more weeks of antibiotic
than 5 cm of diameter therapy
Lesions in the head,
neck, and especially
face

III Disseminated, Treat for at least a week Reduction of Reduction and District and ter- Precise clini-
combined forms; for before surgery and con- infection and prevention of tiary hospitals cal diagnosis
instance, tinue with therapy for a dissemination recurrences and laborato-
osteomyelitis, osteitis, total of 8 weeks of by M ulcerans Reduction of ry exams
joint involvement treatment after surgery the extension
of surgical
excision

Adapted source: WHO/2004 48

in patients who develop osteomyolitis caused by M.
ulcerans. Since patients with lesions that affect the
joints are prone to developing contractures, most of
these patients benefit from actions to prevent disabil-
ities that include activities or exercises to maintain or
improve movements, from the time of diagnosis until
after treatment. If joint movement does not improve
or worsens, the patient should be referred to refer-
ence centers where he can undergo physiotherapy. 2
Recurrence rates after treatment with antibiotics are
lower than 2%, compared with the 16-30% rate of
exclusive surgical treatment. 7,56 These data motivated
a change in the treatment strategy for BU, which was
geared towards surgical treatment until 2004.
MONITORING AND PROGNOSIS
After conclusion of the antibiotic treatment, the
patient should be monitored for at least 10 months so
that cure can be confirmed. Monitoring is also impor-
tant for the diagnosis of possible complications and to
notice any recurrences. 52 Execution of the ten tasks
listed in chart 4 can prevent or minimize disabilities
and should be initiated at diagnosis and continue after
the treatment is concluded, when necessary. 59
The evolution of the disease may vary in severi-
ty. In some areas, ulcers heal slowly with fibrosis and
retraction. In the limbs, retraction can be extensive
and impair their function permanently. Facial lesions
can lead to serious cosmetic deformity or even loss of
the eyeball. Death due to infection by M. ulcerans is
rare, although secondary bacterial infection may
aggravate extensive areas of ulceration. 16 Often, the
general condition of the patient is not affected. 12
Spinocellular carcinomas have been reported to devel-
op in healing areas after BU. 60 Care 59,61 with scars is
very important to reduce skin dryness, fissures, trau-
ma during work or leisure, sunburns, and 47
problems
with the mobility of soft tissue and joints.

An Bras Dermatol. 2010;85(3):281-301.

294 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE

CHART 4: Ten tasks for the prevention of disabilities caused by Buruli ulcer:
“Tasks for individuals affected by Buruli ulcer who wish to prevent disability - I can!”

10 Tasks Key point 1 Key point 2 When to start Frequency? Expected results

Task 1 Early diagnosis - find Undergo treatment Immediately! Daily for 8 Germs will be dead,
Diagnosis other cases of BU as weeks but you will need to
&Treatment early as possible, take other actions to
before many injuries help your body heal
have occurred completely

Task 2 Wash your body Wash hands frequently Now! Daily Stay clean
Hygiene Prevent infections
The body will heal
faster

Task 3 Know which foods Eat foods that you are Now! Daily 2-3 times Wounds heal
Nutrition aid in healing able to

Task 4 Wash with water Wear clean clothes 1 As soon as the Daily, until it Skin is softer and
Wound & Apply oil to keep the Avoid tight dressings wound is discov- heals more flexible
skincare skin flexible (restrictive) and favor ered - even before
those that encourage diagnosis is accom-
movement 2 plished

Task 5 Try to move the Engage in routine Start movements Many times a Normal movement
Movement & affected area and the activities 2 and exercises as day (Every 1-2
Exercise other side as well2 soon as BU is diag- hrs.)
nosed 2

Task 6 When at rest or Position that allows At diagnosis, if Daily Avoid contractures
Position sleeping to stretch drainage of the edema there is any limita- Reduce edema
the wound or scar tion of movement
or edema

Task 7 Raise the affected Dressings from the end At diagnosis, if Most part of Reduces the pain
Edema limb and encourage of the limb upward there is edema the day and and allows complete
movement night, until the movement
edema sub-
sides

Task 8 Soap & Oil Massage & protector 1 As soon as wounds Daily for 1- 2 Mobile, discreet scar
Care with the against skin extension are healed years Complete movement
scar

Task 9 Practice self-care Participate in school, Now! Daily Lead a normal life
Participation Involve relatives work and social activi-
ties

Task 10 Know when help is Know where to look When necessary When neces- Solve problems
Extra help needed for help sary Improve functionality
Use telephone or email
1
Apply light pressure with a sponge; 2 It is not necessary to practice exercises for 10 days after skin graft; movement is beneficial, but can
cause discomfort. Forced movement that causes intense pain is harmful and should be avoided - Modified from Lehman L & Saunderson P,
American Leprosy Missions 08/20/2009
Adapted source: Lehman L et al.59

PREVENTION
Prevention of BU is difficult because there is no the disease or isolation of a specific antigen to devel-
clear knowledge about the forms of transmission of op a vaccine. The Calmette-Guerin bacillus (BCG)

An Bras Dermatol. 2010;85(3):281-301.

Buruli ulcer
appears to offer some short-term protection against
the disease. Even though there is still some debate, 2,7,62
BCG vaccine seems to protect against osteomyelitis.
Due to the absence of efficient tools to control
BU, current control strategies aim at reducing the pro-
longued suffering, disability, and socioeconomic bur-
den associated with the disease. 7,8 In the annual meet-
ing of the WHO for the control and management of
BU, held in Geneva, Switzerland, in March of 2005,
the following control strategies were suggested: 8
• Early detection of cases in communities
through information, education, and communication;
• Prevention of disabilities;
• Education of health workers in communities;
• Case management (a combination of antibi-
otics, surgery, and prevention of disabilities/ rehabili-
tation);
• Laboratory confirmation of cases;
•Standardized storage of data and communica-
tion system using forms BU 01 and BU 02 and a
HealthMapper;
• Strengthening of reference health services;
• Monitoring and evaluation of control activities.
CONCLUSION
Buruli ulcer, caused by Mycobacterium ulcer-
ans, 1 has been reported in more than 30 countries,
295
especially with tropical and subtropical climate, 7 but
its epidemiology remains unclear, even in endemic
countries. For instance, it is recognized as a public
health problem in Uganda, Nigeria, Gabon, Ghana,
Togo, French Guiana, Cameroon, Liberia, Côte
D’Ivoire, Malasia, Papua New Guinea, and Benin. 7 The
limited knowledge about the disease, its focal distribu-
tion, and the fact that it affects mainly rural poor com-
munities contribute to the low reporting of cases.
Similarities between the climate, vegetation and
habits in Brazil and endemic countries suggest that
Brazil may be a likely focus of the disease. Lack of
knowledge about the disease by health porfessionals
makes the identification and epidemiological monitor-
ing of the disease difficult in Brazil. In 2007, the first
case of BU in Brazil was published 13 and, in November
of 2009, 20 McGann et al. reporte the occurrence of a
second case in the Brazilian territory. This shows that
the presence of the disease in national territory is
plausible.
Despite the great knowledge about the clinical
profile of BU in endemic countries, in other areas this
diagnosis may be overlooked. Therefore, physicians
should be educated about BU, because early diagnosis
and proper treatment aid in the prevention of func-
tional disabilities resulting from this infection. 
An Bras Dermatol. 2010;85(3):281-301.
296 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
ACKNOWLEDGEMENTS
The authors would like to thank the initiative of Dr. Kingsley Bampoe Asiedu, physician responsible for the
Global Buruli Ulcer Iniciative/GBUI of the World Health Organization (WHO). Dr. Asiedu alerted us to the
importance of this topic and recommended that an extensive continuing medical education article be written
to train Brazilian dermatologists and physicians in other specialties to diagnose BU in Brazil. He is also
responsible for granting permission to use images from the homepage of the WHO
(www.who.int/buruli/photos/en/index.html).
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38. Hernandez-Pando R, Orozco H, Sampieri A, Pavon L,
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disease (Buruli ulcer). Clin Diagn Lab Immunol. 2002;
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Buruli Ulcer Prevention of disability (POD) [mono
graph on the internet]. WHO. 2006.[cited 2010 Mar
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information/publications/BU-0POD-presentation.pdf
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from: http://www.who.int/classifications/icf/en/
49. Bafende AE, Lukanu NP, Numbi AN. Buruli ulcer in an
AIDS patient. S Afr Med J. 2002;92:437.
50. Johnson RC, Ifebe D, Hans-Moevi A, Kestens L,
Houessou R, Guédénon A, et al. Disseminated
Mycobacterium ulcerans disease in an HIV-positive
patient: a case study. AIDS. 2002;16:1704-05.
51. Duker AA, Portaels F, Hale M. Pathways of
Mycobacterium ulcerans infection: a review. Environ
Int. 2006;32:567-73.
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guidance on the role specific antibiotics in the
management of Mycobacterium ulcerans disease
(Buruli ulcer). Geneva: WHO; c2010 [cited 2010 Mar
29]. Available from: http://www.who.int/buruli/
information/antibiotics/en/index.html
53. Hayman J, McQueen A. The pathology of
Mycobacterium ulcerans infection. Pathology.
1985;17:594-600.
54. Siegmund V, Adjei O, Racz P, Berberich C, Klutse E, van
Vloten F, et al. Dry-reagent-based PCR as a novel tool
for laboratory confirmation of clinically diagnosed
Mycobacterium ulcerans-associated disease in areas in
the tropics where M ulcerans is endemic. J Clin
Microbiol. 2005; 43:271-76.
55. Etuaful S, Carbonnelle B, Grosset J, Lucas S, Horsfield
C, Phillips R, et al. Efficacy of the combination
rifampin-streptomycin in preventing growth of
Mycobacterium ulcerans in early lesions of Buruli ulcer
in humans. Antimicrob Agents Chemother.
2005;49:3182-6.
56. Nienhuis WA, Stienstra Y, Thompson WA, Awuah PC,
Abass KM, Tuah W, et al. Antimicrobial treatment for
early, limited Mycobacterium ulcerans infection: a ran
domized controlled trial. Lancet. 2010;375:664-72.
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298 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
57. Johnson PDR. Should antibiotics be given for Buruli
ulcer? Lancet. 2010;375:618-9. Comment on: Lancet.
2010;375:664-72.
58. Stienstra Y, Dijkstra PU, van Wezel MJ, van Roest MH,
Beets M, Zijlstra IJ, et al. Reliability and validity of the
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59. Lehman L, Saunderson P. Ten Tasks to Prevent
Disability in Buruli Ulcer, Tasks for people affected by
Buruli Ulcer who want to prevent disability - “I Can Do
It!” American Leprosy Missions, 2009. (currently used
in community based POD training and is being made
into a flip chart which is expected to be adopted by
WHO. Examples will be shown at the 2010 Geneva BU
meeting)
How to cite this article/Como citar este artigo: Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE. Buruli
ulcer. An Bras Dermatol. 2010;85(3):281-301.
An Bras Dermatol. 2010;85(3):281-301.
60. Evans MR, Etuaful SN, Amofah G, Adjei O, Lucas S,
Wansbrough-Jones MH. Squamous cell carcinoma
secondary to Buruli ulcer. Trans R Soc Trop Med Hyg.
1999;93:63-4.
61. Minutilli E, Orefici G, Pardini M, Giannoni F, Muscardin
LM, Massi G, et al. Squamous Cell carcinoma secondary
to buruli ulcer. Dermatol Surg. 2007;33:872-5.
62. Portaels F, Aguiar J, Debacker M, Guédénon A, Steunou
C, Zinsou C, et al. Mycobacterium bovis BCG
vaccination as prophylaxis against Mycobacterium
ulcerans osteomyelitis in Buruli ulcer disease. Infect
Immun. 2004;72:62-5.
MAILING ADDRESS / ENDEREÇO PARA CORRESPONDÊNCIA:
Prof. Omar Lupi
Rua Frei Leandro, 16/501 - Lagoa
22470 210 Rio de Janeiro - RJ, Brazil
Fax: 55-21-2522-6346
E-mail: omarlupi@globo.com
Buruli ulcer
QUESTIONS
L
1) What is the etiologic agent of Buruli ulcer?
a) Mycobacterium avinum
b) Mycobacterium chelonei
c) Mycobacterium ulcerans
d) Mycobacterium bovis
2) What is the likely cause of change in the
epidemiology of Buruli ulcer?
a) It has been attributed to flooding, population
growth, mining, wood extraction from
tropical forests, and river damming.
b) Migration from and to rural and urban areas,
leading to the development of new cases in
large urban centers.
c) Change in economic activities leading to the
economic growth of most countries
previously considered endemic.
d) Higher notification of cases in countries
previously not considered endemic
3) How many cases of the disease have been
reported in Brazil?
a) none
b) one
c) two
d) twenty-two
4) Regarding the form of transmission of the
disease, it is incorrect to state the following:
a) An environmental factor associated with slow-
flowing water, to which populations who live
by the water are exposed, might play a role.
b) There are reports of a possible transmission
through insect bites or insects, probably
acquatic insects of the order Hemiptera
(Naucoridae and Belostomatidae). Studies
have shown that the Naucoris mosquito is
naturally colonized by M. ulcerans in
endemic areas.
c) There are no reports of patient-to-patient
transmission.
d) The agent of BU can enter the human body
through several types of trauma, from mild
ones, such as a hypodermic injection, to
severe, such as landmine injuries.
5) It is correct to state the following about the
etiologic agent of BU:
a) This mycobacterium is a predominantly
intracellular BAAR and can live freely in the
environment, especially in acquatic
environments.
b) It is slow growing and needs a specific culture
medium, different from the one used for
other mycobacteria.
c) There is some variation between the strains of
299
M. ulcerans found in different georaphical
areas (Africa, America, Asia, and Australia) that
can be observed with the use of the PCR
technique.
d) There appears not to be a direct relationship
between virulence and the number of IS2404
copies.
6) Mycolactone is a heat-stable exotoxin, lypophilic,
that belongs to the group of macrolides and
causes extensive, chronic and necrotizing damage
to the papillary dermis, subcutaneous fat, and
muscles, resulting in deformity and disability. It is
incorrect to state the following about this molecule:
a) The molecule is active in extremely low
concentrations and is not present in
laboratory cultures.
b) Mycolactone molecules, when injected in
laboratory animals, are capable of producing
massive necrosis similar to that observed in
animals innoculated with M. ulcerans.
c) Mycobacterium marinum and M. ulcerans are
philogenetically close and may share from 98
to 99.8% of their genetic material, but the
production of mycolactone by M. ulcerans
differentiates the two species.
d) M. liflandii also has the IS2404 sequence and
all the genes that codify mycolactone. This is
why it is impossible to distinguish it from M.
ulcerans.
7) The following is not characteristic of the
histopathological evolutionary stages of BU:
a) Late healing stage - fibrosis and atrophic
epidermis.
b) Initial healing stage - without granulomatous
response. Numerous BAAR are still found.
c) Non-ulcerated necrotic stage - the epidermis
is intact, but it is often hyperplastic. The
upper dermis is preserved, with varying
degrees of colagen degeneration and discreet
infiltration of inflammatory cells with the
presence of denucleated adipose cells, called
“ghost cells”.
d) Ulcerated necrotic stage: there is loss of the
epidermis and attempt of reepitelization in
the borders of the ulcer. The epidermis is
hyperplastic, there is minimal inflammation,
and presence of numerous BAAR.
8) What is the main factor that determines which
type of clinical lesion we will find in a patient?
a) Strain of the mycobacterium causing the disease
b) Work activity of the patient
c) Patient's immunity
d) Evolution time
An Bras Dermatol. 2010;85(3):281-301.
300 Boleira M, Lupi O, Lehman L, Asiedu KB, Kiszewski AE
9) What is the incubation period of the disease?
a) 3 months
b) 7 days
c) 1 year
d) 3 weeks
10) Buruli ulcer can present with a large area of
marked induration, diffuse edema in the arms
and legs or a well-demarcated plaque. It is correct
to state the following about this clinical phase of
the disease:
a) It is also called disseminated BU.
b) Plaques are raised, indurated, painless,
hyperpigmented and smaller than 2 cm.
c) It does not progress to an ulcer.
d) It never affects the entire limb, only part of it.
11) It is incorrect to state the following about the
clinical profile of BU:
a) Strains of M. ulcerans isolated from various
clinical forms of BU in a particular
geographical region appear identical,
suggesting that host factors may play an
important role in the determination of the
clinical presentations of the disease.
b) The base of the initial ulcer usually contains a
whitish, foamy secretion and sometimes it
can form crusts.
c) One of the consequences of an extensive
ulcer is the involvement of bone tissue, with
high risk of osteomyolitis and later
deformities or even amputations.
d) Due to the local immunological properties of
mycolactone, the disease progresses with
intense pain, high fever, and systemic symptoms.
12) It is correct to state the following about the
healing phase of the disease:
a) The cosmetic aspect of the scar seldom
causes social problems or withdrawal from
daily activities.
b) Permanent disabilities affect about half of the
patients.
c) The risk of disability increases with the
development of osteomyelitis during the
course of the disease.
d) The involution of lesions may result in
atrophic sequelae or scars with contractures
and impairment of the function of limbs
when lesions occur on extensor areas.
13) Many diseases can be possible differential
diagnoses of Buruli ulcer. It is correct to state the
following:
a) In West Africa, BU can be mistaken for
onchocercoma and nodular leishmaniasis.
b) The presentation of the disease with plaques
and edema is completely different from any
profound mycosis. Differential diagnosis with
this class of diseases is done when the patient
An Bras Dermatol. 2010;85(3):281-301.
is in the ulcerative phase of BU.
c) Tropical ulcer is rarely confused with BU
because it more commonly affects the upper
limbs; however, this diagnosis should always
be contemplated.
d) Leishmaniasis is an important differential
diagnosis, but not in South America, where it
is a rare occurrence.
14) All the following are clinical criteria for suspicion
of BU, except:
a) Presence of chronic lesion
b) Regional lymphoadenopathy
c) Edema on painful joint, suggesting bone
involvement
d) Patient who lives in or visisted an endemic area
15) Laboratory diagnoses are not commonly used to
make decisions about treatment due to
operational and logistic difficulties. It is incorrect
to state the following about the possile
techniques employed:
a) Laboratory diagnosis can also be used to
confirm clinical diagnosis retrospectively on
swabs and tissues removed during treatment.
b) Bone tissue curetage should be performed to
confirm osteomyelitis.
c) Histopathology is useful for differential
diagnosis when the results of other methods
are negative. It is up to 90% sensitive.
d) Culture of M. ulcerans takes from 6 to 8
weeks and is approximately 100% sensitive.
16) Which of the following corresponds to
recommendations of the WHO for the proper
treatment of BU?
a) Surgery should not be performed to remove
necrotic tissue if wound healing causes joint
impairment and cosmetic burden for the patient.
b) Due to the high rate of complications per and
post-surgery, surgery is not performed to
correct defects, contractures, and the
function of the affected joints. Physiotherapy
is used for these purposes.
c) Association of rifampicin and streptomycin
for eight weeks as a first-line treatment for all
forms of the active disease.
d) The recommended doses of rifampicin and
streptomycin are: rifampicin, 15mg/kg of
body weight, taken orally, daily, for eight
weeks; streptomycin, 10 mg/kg, taken
intramuscularly, daily, for eight weeks. This
drug is contraindicated for pregnant women.
17) It is incorrect to state the following about
alternative treatments of BU:
a) Many antimicrobial drugs (rifampicin,
aminoglycosides, macrolides, and quilones)
appear to be effective based on clinical
impressions.
Buruli ulcer 301

b) Studies (6) have shown that macrolides, administered in two doses, appears to offer
quilonones, and aminoglicosides inhibit the protection against the disease.
in vivo growth of M. ulcerans. c) In the absence of adequate tools to control
c) Treatment combinations with aminoglycosides BU, current control strategies aim at reducing
are more efficient than those without this drug. the prolongued suffering, disability, and
d) There is a beneficial effect of clofazimine on socioeconomic burdens associated with the
M. ulcerans. disease.
d) Early detection of cases in communities and
18) It is correct to state the following about the implementation of disability control were
prevention of disabilities: established by the WHO in 2005.
a) After the implementation of the so-called “10
tasks”, the benefit of physiotherapy started
being questioned.
b) Movement of the affected limb from the time
of diagnosis is essential for the prevention of
disabilities.
Answer key
c) The “10 tasks” recommended by the WHO Occupational dermatosis.
should only be executed by competent 2010; 85(2):137-47.
professionals in reference centers.
d) The main cause of disabilities is the level of 1 c 11 a
immunological response against the infection 2 d 12 a
and is not related with a delay in treatment. 3 d 13 c
4 d 14 c
19) After treatment is completed, the patient should 5 c 15 c
be monitored: 6 a 16 d
a) For at least 6 months 7 d 17 c
b) Only if there are functional complications
8 a 18 b
c) Every two years, after the first year
d) Monthly, for at least 10 months 9 b 19 c
10 b 20 b
20) Prevention of BU is complicated because there is
no clear knowledge about the forms of Papers
transmission of the disease or isolation of a Information for all members: The EMC-
specific antigen for the development of a vaccine. D questionnaire is now available at the home-
In spite of this, it is incorrect to state the page of the Brazilian Annals of Dermatology:
following about attempts to prevent the disease: www.anaisdedermatologia.org.br. The deadline
a) Patients who received the BCG vaccine are for completing the questionnaire is 60 days
less likely to develop osteomyelitis.
from the date of online publication.
b) The bacillus Calmette-Guerin (BCG), when

An Bras Dermatol. 2010;85(3):281-301.